Introduction

Guselkumab (GUS), interleukin-23p19 subunit inhibitor, has been approved for moderately to severely active Crohn’s disease (CD) in Japan. CNTO1959CRD3003 is a Phase 3, open-label, multicenter study designed to evaluate the safety and efficacy of GUS in Japanese patients with moderately to severely active CD. We report the efficacy of GUS on small bowel lesions.

Aims & Methods

The primary objective was to evaluate safety, and the secondary objective was to evaluate the efficacy of GUS at week 48 (W48). An exploratory objective was to assess the efficacy of GUS for small bowel lesions, evaluated using retrograde balloon-assisted enteroscopy (BAE). Eligible patients in this study were patients with active ileocolonic CD or small bowel CD, as clarified by endoscopic evaluation. GUS 200 mg was administered intravenously on Weeks 0, 4, and 8 and subcutaneously every 4 weeks from week12 until W44. As optional, small bowel lesions were assessed using modified simple Endoscopic Score for Crohn’s Disease [mSES-CD], excluding stricture evaluation. The sum of the proximal ileum (10-300 cm from ileocecal valve) and terminal ileum sub-scores was defined as a partial modified SES-CD (pmSES-CD). Within patients with pmSES-CD score of 4 or more at baseline, those with a score reduction of 50% at W48 from the baseline were defined as endoscopic responder; a pmSES-CD score of less than 4 points was defined as ulcer-free, and a pmSES-CD score of 0 was defined as complete mucosal healing.

Results

A total of 38 patients were enrolled and received GUS treatment. Most participants were male (24/38; 63.2%), and the median age was 40.5 (range: 20-69) years. This group included 8 with ileal type, 9 with colonic type, and 21 with ileocolonic type. The median duration of CD was 7.97 (0.4–33.0) years. Overall, 33/38 patients (86.8%) experienced an adverse event (AE) and 3/38 (7.9%) experienced a serious AE. There were no CD-related hospitalizations or surgeries, and no new safety concerns were identified regarding GUS treatment through W48.
Among the 38 patients, 15 patients were evaluated for small bowel lesion using retrograde BAE, defined as the small bowel (SB) group. Among these, the median age was 41.0 (24-69) years, and the median duration of CD was 2.92 (0.4-16.9) years. The median pmSES-CD was 8.0 (0-14) at baseline and 5.0 (0-13) at W48. 7/15 patients (46.7%) were endoscopic responders, 4/15 patients achieved ulcer-free (26.7%), and 2/15 patients (13.3%) achieved complete mucosal healing at W48 (Table.1). Three participants (20.0%) showed improvement of 5 points or more in the lesions of the proximal ileum as measured by pmSES-CD. Two of three ileal type patients achieved ulcer-free at W48. No AE of strictures were reported through W48.

Table 1. Result of efficacy of guselkumab treatment on small bowel lesions.

Conclusion

Overall, this study showed that GUS is well-tolerated and effective for treating patients with moderately to severely active CD, and the results also suggested the effectiveness of GUS in small bowel lesions.

Disclosure

TH: Grant: EA pharma Co. Ltd., AbbVie GK, Pfizer Inc., Mitsubishi Tanabe Pharma Corporation, Kyorin Pharmaceutical Co. Ltd., JIMRO Co.Ltd, Mochida Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co. Ltd., Zeria Pharmaceutical Co. Ltd., Nippon Kayaku Co. Ltd., Kissei Pharmaceutical, Boston Scientific
Consulting fees: EA pharma Co. Ltd.,AbbVie GK,Pfizer Inc.,Mitsubishi Tanabe Pharma Corporation,Takeda Pharmaceutical Co. Ltd.,Gilead Sciences, Inc.,Eli Lilly and Co.,Janssen Pharmaceutical K.K.,Bristol Myers Squibb,Abivax
Payment or honoraria for lectures, presentations, speakers;
EA pharma Co. Ltd.,AbbVie GK,Pfizer Inc.,Mitsubishi Tanabe Pharma Corporation,Kyorin Pharmaceutical Co. Ltd.,JIMRO Co.Ltd,Mochida Pharmaceutical Co., Ltd.,Takeda Pharmaceutical Co. Ltd.,Zeria Pharmaceutical Co. Ltd.,Nippon Kayaku Co. Ltd.,Janssen Pharmaceutical K.K.
TK: Grant: Abbie GK, Alfresa Pharma Corporation, EA Pharma, Gilead Sciences, Inc. Nippon Kayaku Co., Ltd., Eli Lilly Japan K.K., Mochida Pharmaceutical Co., Ltd., Janssen Pharmaceutical K.K., Pfizer Japan Inc., Sekisui Medical, Takeda Pharmaceutical Co., Ltd., Bristol-Myers Squibb, Mitsubishi Tanabe Pharma Corporation, Zeria Pharmaceutical Co., Ltd., JIMRO Co., Ltd., Consulting fees :Takeda Pharmaceutical Co., Ltd., Alfresa Pharma Corporation, Zeria Pharmaceutical Co., Ltd., Kyorin Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Abbie GK, Pfizer Japan Inc., Janssen Pharmaceutical K.K., JIMRO Co., Ltd., Galapagos, Takeda Pharmaceutical Co., Ltd., Expert testimony : EA Pharma Co., Ltd., KISSEI Pharmaceutical Co., Ltd, Takeda Pharmaceutical Co., Ltd., Pfizer Japan Inc., Nippon Kayaku Co., Ltd., Alfresa Pharma Corporation, Abbie GK, Mochida Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Janssen Pharmaceutical K.K.
KW: Consulting fees: EA Pharma Co., Ltd., Payment or honoraria for lectures, presentations, speakers: Takeda Pharmaceutical Co., Ltd., AbbVie Japan Co., Ltd., EA Pharma Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., JIMRO Co., Ltd.
Participation on a Data Safety Monitoring Board or Advisory Board: Takeda Pharmaceutical Co., Ltd., Leadership or fiduciary role in other board, society, committee : Japanese Society of Gastroenterology, Japanese Society of Gastrointestinal Endoscopy, Japanese Gastroenterological Association, Japan Society of Coloproctology, Japanese Society of Mucosal Immunology, Japan Society for Inflammatory Bowel Disease, Japanese Society of Small Intestinal Disease, Japanese Association for Capsule Endoscopy, Research group of intractable IBD, the Ministry of Health, Labor and Welfare in Japan
KO All support for the present manuscript : J&J Innovative Medicine, Payment or honoraria for lectures, presentations, speakers: AbbVie Inc, EA Pharma Co.,Ltd, Janssen Pharmaceutical, KYORIN Pharmaceutical, Mitsubishi Tanabe Pharma, MOCHIDA PHARMACEUTICAL, Nippon Kayaku Co.,Ltd, OLYMPUS CORPORATION, Takeda Pharmaceuticals, Zeria Pharmaceutical Co., Ltd.
ME: Grant: Kyorin Pharmaceutical Co. Ltd, Payment or honoraria for lectures, presentations, speakers: AbbVie GK, Mitsubishi Tanabe Pharma, EA Pharma Co., Ltd, Janssen Pharmaceutical, Takeda Pharmaceuticals, Pfizer Japan Inc., Gilead Sciences Inc., Mochida Pharmaceutical Co. Ltd
TO: Payment or honoraria for lectures, presentations, speakers: AbbVie GK., Takeda Pharmaceutical Co. Ltd., and KISSEI Co. Ltd
NH: Expert testimony : J&J Innovative Medicine
TM: None
TS, KM, MC, HH and SY are employees of Johnson & Johnson.

Clinical Case Summary

An 18-year-old female was diagnosed with very early-onset Crohn’s disease (CD) in 2008. Due to steroid dependence, adalimumab 40 mg biweekly was initiated in 2019, with escalation to 40 mg weekly in February 2023 following secondary loss of response. In November 2023, despite clinical and biochemical remission (CRP <0.5 mg/L, fecal calprotectin <50 µg/g), the patient developed painful purpuric and ulcerated lesions on both lower limbs. Histological examination of a skin biopsy confirmed leukocytoclastic vasculitis (LCV), revealing perivascular neutrophilic infiltrates, nuclear debris, and fibrinoid necrosis in post-capillary venules. Infectious and autoimmune screening, including ANA, antiphospholipid antibodies, p-ANCA, and c-ANCA, were negative. Following consultation with an immunologist, adalimumab was discontinued, and oral prednisone 25 mg/day was initiated. However, the clinical course was complicated by a skin abscess, which was treated with oral amoxicillin/clavulanate (1 g three times daily for 3 days). As vasculitic lesions worsened, the patient was hospitalized, and prednisone was increased to 50 mg/day. Intravenous cefazolin (2 g every 8 hours for 5 days) was also administered, resulting in stabilization and partial clinical improvement. A multidisciplinary team, including a gastroenterologist, immunologist, and dermatologist, opted to initiate off-label treatment with upadacitinib 30 mg/day, a selective Janus kinase 1 (JAK1) inhibitor. After four weeks, the patient showed improvement in the vasculitic lesions, and corticosteroid therapy was tapered. At the six-month follow-up, the patient remained on upadacitinib monotherapy, with sustained clinical and biochemical remission of both CD and LCV, without any adverse events. This case highlights the potential of JAK1 inhibition as an effective and safe therapeutic option for leukocytoclastic vasculitis in patients with Crohn’s disease.

References

Photographic documentation of the clinical case:
1. Images showing the initial presentation of petechial and purpuric lesions on the lower limbs.
2. Images of severe vasculitis characterized by confluent and ulcerated lesions.
3. Images documenting cutaneous healing following upadacitinib treatment.

Introduction

Mirikizumab is a monoclonal antibody directed against the p19 subunit of interleukin (IL)-23 approved for the management of patients with moderate-to-severe ulcerative colitis (UC). Currently, there is no large study supporting the effectiveness of mirikizumab in UC in a real-life setting.

Aims & Methods

This study aims to evaluate the effectiveness and safety of mirikizumab in real-life setting. This was a retrospective multicenter cohort study of a prospectively collected database including adult patients with confirmed diagnosis of UC treated with mirikizumab according to clinical practice. Patients were enrolled in three third-level italian centers (San Raffaele Hospital, Humanitas Research Hospital, and Federico II Hospital) from June 2024 to February 2025. All patients with at least 3 months of follow-up after therapy initiation were eligible. The primary outcome was the clinical remission rate (defined as partial Mayo Score (pMS) < 2 with a rectal bleeding subscore of 0) at week 12. Secondary outcomes included changes in bowel urgency (measured by the Numeric Rating Scale (NRS) urgency score), changes in serum C-reactive protein (CRP) and fecal calprotectin (FC) levels from week 0 to 12, safety profile of mirikizumab during induction therapy.

Results

In total 100 patients (60% male, with median age 48.53 ± 15.36) with UC were included. Most patients had a left-sided colitis (55, 55%) or a pancolitis (41, 41%). Most patients (81, 81%) were already treated with at least one advanced therapy before starting mirikizumab (including 28 patients treated with ustekinumab, 28%). A fifth of patients (19, 19%) were exposed to ≥ 4 advanced therapies. A significant reduction in pMS was observed from baseline to week 12 (median [IQR]: 4.0 [1.75–6.0] vs. 2.0 [0.0–4.0]; Wilcoxon signed-rank test: W = 312, Z = -5.35, p < 0.00001, n = 69) with 48 (48%) patients reaching clinical remission at week 12. Moreover, a significant improvement in bowel urgency was observed from baseline to week 12 (t(98) = 6.58, p = 2.28×10⁻⁹), with a moderate-to-large effect size (g = 0.66). From baseline to week 12, both FC and CRP levels showed significant reductions following treatment (FC: V = 1153.00, p = 2.4×10⁻⁵, r = 0.67; CRP: V = 680.00, p = 0.03, r = 0.37). Effect sizes were large for FC and moderate for CRP with paired data from 53 and 47 patients being analyzed, respectively. In total, 39 patients (39%) underwent extended induction while 3 patients (3%) discontinued the drug at week 12. There were no adverse events leading to discontinuation or death. Two mild adverse events were reported (upper respiratory tract infection in 1 patient and pyrexia in 1 patients). No significant changes were observed in liver aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels over time (AST: χ²(2) = 0.21, p = 0.90, W = 0.005; ALT: χ²(2) = 3.73, p = 0.16, W = 0.08).

Conclusion

This is the largest study demonstrating the effectiveness and safety of mirikizumab in inducing clinical remission in patients with UC in a real-life setting. Patients treated with mirikizumab achieved a significant reduction in bowel urgency, FC and CRP levels. No statistically significant increase in liver toxicity was detected during the induction treatment.

Disclosure

F. D'Amico. OM Nardone, A. Zilli, M. Allocca, S. Danese, L. Peyrin-Biroulet and A. Armuzzi have served as speaker and advisory board member for Lilly

Introduction

Interleukin (IL) inhibitors are monoclonal antibodies that have been shown to be effective in inducing and maintaining remission in moderate to severe ulcerative colitis (UC).
Ustekinumab (UST) was approved in the EU for the treatment of UC in 2019 and binds specifically to the p40 protein subunit of IL-12 and IL-23. Mirikizumab (MIRI) was approved 4 years later and selectively binds to the p19 subunit of the IL-23 cytokine. By binding to the IL subunits, the interaction with the IL-23 receptor is inhibited.
In this study, we compared the response rate to induction therapy with UST and MIRI in patients with moderately to severe UC.

Aims & Methods

All patients with active UC who began induction therapy with UST or MIRI at our outpatient clinic between 2019 and 2024 were analyzed retrospectively with a follow-up period until April 2025. Patients who received the IL-23 inhibitor due to a disease other than UC or following a prednisolone therapy exceeding 20 mg and patients with pouchitis were excluded from the study.
We determined the response to IL-23 therapy 8 to 24 weeks after the start of treatment and documented this either as clinical remission (Mayo-Score ≤1), improvement (Mayo-Score reduction by at least 3 points), inadequate response (Mayo-Score reduction between 0 and 2) or no response (lack of benefit, switch to another medical class or colectomy).
We examined the levels of calprotectin in the stool 0 to 24 weeks before the start of IL-23 therapy up to 24 weeks after initial administration.
Our study included 40 patients treated with UST and 23 patients treated with MIRI, in the latter group 26% have previously been treated with UST. Patients in both groups were similar in age (mean age, 47.75 vs. 44.59 y; P 0.28), gender, disease duration (mean duration, 11 vs. 9 y; P 0.32), and extent of disease (pancolitis, 40% vs. 48%).

Results

After completion of induction, 25% in the UST group and 57% in the MIRI group reached clinical remission. MIRI after UST achieved clinical remission in 67%. Improvement was shown in 20% vs. 30%, UST vs. MIRI. For UST, 5% were non-responder. For MIRI, no non-responder was noted. In general, the difference between the pre- and post-induction Mayo-Score is significantly higher for MIRI, indicating a better response to the newly started drug (mean Mayo-Score difference, UST vs. MIRI, 2.95 vs 4.5; P 0.0003)
The mean calprotectin level before treatment was not significantly different (mean calprotectin, UST vs. MIRI, 1652 vs. 2452 mg/kg; P 0.17). The post-treatment calprotectin level was significantly higher for UST vs. MIRI (mean calprotectin, 1092 vs. 278 mg/kg; P 0.0083).

Conclusion

Mirikizumab is an effective induction treatment for patients with active ulcerative colitis, including those who previously did not respond adequately to Ustekinumab therapy.